Paneth cell SIRT1 regulates intestinal tissue homeostasis

Intestinal epithelial homeostasis is maintained by a complex interplay between different epithelial cells, gut microorganisms, and immune cells. Disruption of this interplay contributes to inflammatory and immune diseases associated with gut microbiome dysbiosis. A genetic factor that modulates the interactions between gut epithelium, microbiota and immune cells is sirtuin 1 (SIRT1), the most conserved mammalian NAD+-dependent protein deacetylase. We and others have shown that deficiency of intestinal epithelial SIRT1 leads to intestinal inflammation, disruption of gut microbial composition, and altered susceptibility to environmentally induced colitis. Recently we generated a Paneth-cell specific SIRT1 KO mouse model (SIRT1 PKO). Similar to mice with SIRT1 deficiency in whole intestinal epithelium, SIRT1 PKO mice had increased abundance as well as hyperactivation of Paneth cells in vivo and in cultured intestinal organoids. Single-cell RNA-seq of whole intestinal cell populations confirmed that deletion of Paneth cell SIRT1 significantly increases the abundance of Paneth cells. This increase was accompanied with an elevated abundance of intestinal stem cells, transition amplifying cells, and enterocytes. Consistently, SIRT1 PKO mice were able to better maintain their intestinal epithelial integrity during aging and were protected from chemically induced colitis compared to control mice. Deletion of SIRT1 in Paneth cells further induced profound alterations in gut microbiota. Using microbiota-depleted mice and fecal transplantation, we demonstrate that Paneth cell SIRT1 deficiency ameliorates colitis through the gut microbiota. Collectively, our findings uncover an unanticipated function of Paneth cell SIRT1 in conferring sensitivity of the gut epithelium to stress.